Skin and soft tissue infections (SSTI) are one of the most common problems encountered in clinical practice and affect millions of individuals annually in the United States. These infections may range from uncomplicated superficial SSTI to life-threatening complicated deep SSTI. Treatment of SSTI has been significantly complicated by the increasing emergence of multidrug-resistant pathogenic bacteria. As a result, there is a pressing need for the development of new therapeutic approaches. The objective of this proposal is to investigate the utility of a non-antibiotic approach, antimicrobial blue light theray, for multidrug-resistant SSTI. Specifically, we propose to: Aim 1: Demonstrate the efficacy of antimicrobial blue light therapy for superficial or deep SSTI in rodents infected with Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) or Gram-negative multidrug-resistant Pseudomonas aeruginosa. We will use superficial impetigo in mice and deep incisional surgical site infections in rats as the representative models of superficial and deep SSTI, respectively. Both immunocompetent and immunocompromised mice/rats will be tested. Bacterial inocula of 3x105 and 3x107 colony-forming units/rodent will be used to represent the infections caused by a low and a high inoculum, respectively. We will use the in vivo bioluminescence imaging technique to quantitatively and noninvasively monitor in real time the extent of infections in living animals. Blue light (405-415 nm wavelength) will be initiated at 30 min, 24 h, and 48 h after bacterial inoculation, respectively. The efficacy found with blue light therapy will be compared with that of clinically used antibiotics for SSTI. Aim 2: Determine the potential side effects of antimicrobial blue light therapy for SSTI. We will first compare the susceptibilities to blue light inactivation in vitro between pathogenic bacteria and host cells. We will also determine whether the pathogenic bacteria can develop resistance to blue light inactivation. The experiment will be implemented by carrying out repeated cycles of sub-lethal blue light inactivation of bacteria in vitro followed by bacterial regrowth. Finally, wewill investigate whether blue light is genotoxic to host cells by using the alkaline comet assay after irradiation of host cells in vitro and in vivo. Successful completion of these specific aims will provide the foundation required to assess the efficacy (Aim 1) as well as the potential side effects (Aim 2) of antimicrobial blue light therapy for SSTI, and will help establish protocols for the use of this prophylaxis/therapeutic option. Given the significant drawbacks in current management of multidrug-resistant SSTI, this new technology using blue light exhibits great potential.